The broad objective of this research project is to elucidate the mechanism by which ventricular fibrillation (VF) is maintained in normal hearths and in hearts with ischemia and infarction. Understanding these mechanisms is essential for devising improved therapies for preventing sudden cardiac death. We will use two complimentary preparations; optical mapping in isolated perfused whole pig hearts and intramural electrical mapping in slabs of pig left ventricle. Specific Aim 1. Investigate VF mechanisms in normal hearts. We will map VF optically from the entire epicardium using a new imaging technique. Using novel analysis methodology, we will detect the occurrence of propagation block and test two alternative hypotheses: (1) regions of block correlate with areas of non-uniform intrinsic action potential duration (APD) and (2) rate-dependent repolarization instabilities cause escalating beat-to-beat APD variations that eventually culminate in block. We will also map electrically from three orthogonal sensory arrays (two of which are intramural) in isolated left ventricular slabs. We will test the hypothesis that long-lived intramural reentrant sources are continuously present during VF. Specific Aim 2. Investigate VF mechanisms in hearts with regional acute ischemia. We will create an ischemic region by ligating a coronary artery. We will test the hypothesis that: (1) VF in the non-ischemic region is similar to control. (2) Activation rates in the ischemic and non- ischemic regions differ, causing a functional for wavefronts moving from region to the other. (3) New wavebreak formation is more common in the ischemic border zone than elsewhere. However, these wavebreaks do not contribute to VF in the non-ischemic region. Specific Aim 3. Investigate VF mechanisms in hearts with subacute and chronic infarction. We will study in animals with transmural infarcts 3 and 30 days old. We will test the hypotheses that (1) In the animals with 3-days infarcts, VF dynamics in the non-infarcted region are similar to control. (2) In the animals with 3-day infarcts, VF dynamics in the non- infarcted region are similar to control. (2) In the animals with 30-day infarcts, remodeling changes VF dynamics so that the patterns resemble those in hypertrophied hearts (slower, generally more organized). (3) New wavebreak formation is more common near the border of the infarct than elsewhere. However, these wavebreaks do not contribute to CF in the non-infarcted tissue.